Rhodium-catalyzed oxidative C2-acylation of indoles with aryl and alkyl aldehydes

Article abstract of DOI:10.1039/c2cc31351k

A rhodium-catalyzed oxidative C2-acylation of indoles with aryl and alkyl aldehydes via C-H bond activation is described. The reaction is highly atom-economic and provides easy access to a wide variety of 2-aroylindoles.

Full text of DOI:10.1039/c2cc31351k

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Rhodium-catalyzed oxidative C2-acylation of indoles with aryl and alkyl
aldehydesw
Bing Zhou,z Yaxi Yangz and Yuanchao Li*
Received 23rd February 2012, Accepted 26th March 2012
DOI: 10.1039/c2cc31351k
A rhodium-catalyzed oxidative C2-acylation of indoles with aryl
and alkyl aldehydes via C–H bond activation is described. The
reaction is highly atom-economic and provides easy access to a
wide variety of 2-aroylindoles.
variety of acyl electrophiles on the 2-lithioindole species17 or
palladium-catalyzed coupling and cyclization reactions.18 However,
these approaches present intrinsic drawbacks, mainly harsh
reaction conditions or the requirement for highly functionalized
precursors. Therefore, the development of novel and highly
efficient methods to synthesize 2-aroylindole is highly desirable
for drug discovery. Given the prevalence of 2-aroylindoles in
medicinal chemistry and pharmaceutical industries, we became
interested in exploring the first rhodium-catalyzed highly regio-
selective oxidative C2-acylation of indole with aryl or alkyl
aldehydes via direct sp2 C–H bond cleavage, the development of
which is reported herein.
Although arylations of alkenes and alkynes1 have been well
explored in the area of C–H bond functionalization, analogous
additions across polar C–O2 or C–N3 multiple bonds remain
relatively unexplored. Murai, Takai, and co-workers2a–c made
significant contributions after carrying out the addition of aryl
C–H to aldehydes and Shi2d successfully extended this method
to the addition of 3-pyridinyl C–H bonds to aldehydes. In 2009,
Cheng4 reported a palladium-catalyzed coupling reaction of
2-arylpyridines and aryl aldehydes to afford aryl ketones
through a pyridine-directing group. Deng and co-workers5
also demonstrated a palladium-catalyzed coupling reaction of
2-arylpyridines and benzylic or aliphatic alcohols using peroxide
as the oxidant. Recently, Ellman, Shi and co-workers6 reported
Rh-catalyzed addition reactions of the C–H bond of arylpyridines
to aldimine derivatives. Kim and co-workers7 developed the
rhodium-catalyzed oxidative acylation of benzamides with
aryl aldehydes. Several studies8 on the palladium-catalyzed
oxidative acylation of anilides with benzylic alcohols or aldehydes
have been reported. More recently, Li and Shi9 also described the
Rh-catalyzed direct addition of the C–H bond of 2-arylpyridines
to ethyl 2-oxoacetate and aryl aldehydes. Martin and co-workers10
reported the Pd-catalyzed synthesis of benzocyclobutenones
and a,b-substituted styrenes from a-aryl aldehydes via C–H
functionalization.
We initiated our investigation by exploring the coupling of a
variety of N-substituted indoles (1a–f) with benzaldehyde (2a)
(Table 1). The choice of indole protecting group was found to
be crucial (Table 1, entries 1–6), with N,N-dimethylcarbamoyl
being optimal (Table 1, entry 1). We were pleased to find that
Table 1 Selected optimization of the reaction conditionsa
Entry
R
Indoles Solvent Oxidant
Yield (%)b
1
2
3
4
5
6
7
8
(CH3)2NCO 1a
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
PhMe
t-BuOH Ag2CO3
CH2Cl2 Ag2CO3
CH2Cl2 Ag2CO3
CH2Cl2 Ag2CO3
CH2Cl2 Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Cu(OAc)2
K2S2O8
75
0c
CH3
Ac
Boc
Ts
1b
1c
1d
1e
1f
0c
0c
0c
H
0c
The indole nucleus is a ubiquitous structural motif in a number
of synthetic and naturally occurring bioactive compounds.11 In
particular, the 2-aroylindole moiety is presented in several potent
tubulin polymerization inhibitors,12 histone deacetylase class I/II
inhibitors,13 peroxisome proliferator-activated receptor (PPAR)
agonists,14 cyclooxygenase-2 (COX-2) inhibitors15 and platelet-
derived growth factor (PDGF) receptor kinase inhibitors.16 The
common route to 2-aroylindole involves the direct addition of a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
(CH3)2NCO 1a
20
o15
9
benzoquinone o15
10
11
12
13
14
15
16f
t-BuO2H
Ag2CO3
o15
40
65
84
60d
0e
93
a
Conditions: 1a–f (1 equiv), 2a (2 equiv), Cp*Rh(MeCN)3(SbF6)2
(5 mol%), and oxidant (2 equiv) were dissolved in the solvent (0.1 M)
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai
201203, PR China. E-mail: ycli@mail.shcnc.ac.cn
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc31351k
b
and heated at 85 1C for 24 h in a sealed tube. Yield isolated by
column chromatography. No reaction happened at the C2 or C3
c
d
position. Using [Cp*RhCl2]2 and AgSbF6 as the catalyst. Using
e
f
[Cp*RhCl2]2 as the catalyst. 3 A molecular sieves were used.
z These authors contributed equally to this work.
c
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Chem. Commun., 2012, 48, 5163–5165 5163

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heating the coupling partners in THF with the catalyst in the
presence of Ag2CO3 as an oxidant yielded compound 3a in 75%
yield (Table 1, entry 1). However, the use of other oxidants,
such as Cu(OAc)2, K2S2O8, benzoquinone, and t-BuO2H, were
relatively ineffective in the coupling of 1a and 2a (Table 1,
entries 7–10). A screen of solvents revealed CH2Cl2 to be
superior to THF (Table 1, entries 11–13). Use of a cationic
catalyst, derived from [Cp*RhCl2]2 and AgSbF6, or related
non-cationic catalyst, [Cp*RhCl2]2, led to lower or no reactivity
respectively (Table 1, entries 14–15). Finally, the best results
were obtained by adding 3 A molecular sieves to afford the
desired 3a in 93% yield, as shown in entry 16. It is noteworthy
to mention, by using the N,N-dimethylcarbamoyl unit as a
directing group, the C–H at the 3-position was untouched19
although it was found to be active in some transformations.20
The regioselectivity of this transformation was further confirmed
by removing the N,N-dimethylcarbamoyl unit of 3a in ethanolic
KOH to provide 3a–l21 in 98% yield (Scheme 1).
that, differing from the previous results,7,9 the electronic nature
of the substituents on the phenyl ring did not play a key role
(3g to 3t) and all the aldehydes showed a good reactivity. For
example, the coupling of benzamide 1a and aldehydes 2g–2m
with para-substituted electron-donating or electron-withdrawing
groups (Me, OMe, NO2, CF3, COCH3, CHO and COOMe) gave
the corresponding products 3g–3m in good to excellent yields
(50%–92%). Moreover, halogen-substituted aldehydes 2n and 2o
were compatible under optimal reaction conditions furnishing
the corresponding products 3n and 3o in good yields, which
provided the opportunity for further transformation through
standard cross-coupling strategies. 2-Naphthylaldehyde (2u) also
underwent the sp2–sp2 coupling reaction to afford product 3u in
excellent yield (90%). In addition, the heterocyclic aldehydes 2v
and 2w also participated in the oxidative coupling to furnish 3v
and 3w in good yields (85% and 73%). Particularly remarkable is
the participation of alkyl aldehydes in this reaction, given the
small number of precedents22 and the lower reactivity of this kind
of aldehyde in oxidative acylation reactions. Under the standard
reaction conditions, the challenging n-butyraldehyde (2x) and
cyclohexanal (2y) could also undergo this coupling reaction
smoothly to provide product 3x and 3y in 70% and 60% yield,
respectively. Interestingly, coupling with indole 1a and paraform-
aldehyde gave the 2,20-biindolyl product 3z with complete
regiocontrol in 54% yield, instead of indole-2-carboxaldehyde
or 2,30-biindoles which have recently been reported by the
oxidative homocoupling of indoles.23 We speculate that due to
the facile C2 directed metalation with the rhodium(III) catalyst,
in the absence of an active aldehyde component, a C2 rhodated
bisindolyl intermediate forms, which would afford 3z24 through
a reductive elimination (Scheme 3).
Having established the optimized reaction conditions, the
substrate scope was examined with respect to the aldehyde
(Scheme 2). First, various electron-donating and electron-
withdrawing groups are introduced to the phenyl part of the
aldehyde at the para-, meta- or ortho-position. It was found
Scheme 1 Hydrolysis of 3a.
Encouraged by these results, we further examined this
coupling reaction with a variety of indoles 1g–1n and aldehyde
2a under identical reaction conditions to further explore the
substrate scope and limitations of this process (Scheme 4).
Both electron-withdrawing (1g, 1h) and electron-donating (1i, 1m)
indoles were readily converted to the corresponding products in a
good to excellent yield, as were the bromo- or fluoride-substituted
substrates (1j, 1k and 1l). In addition, the 7-azaindole substrate
(1n) was also found to be favorable in this reaction and provided
product 4n in 45% yield.
In summary, we have developed an efficient rhodium-catalyzed
oxidative C2-acylation of indoles via a selective C–H activation
under mild conditions. In this transformation, both electron-poor
and electron-rich aryl and alkyl aldehydes are highly effective.
Consequently, this reaction should be useful for rapid, atom-
economical preparation of 2-aroylindoles directly from aldehydes.
In addition, we performed the catalytic, dehydrogenative,
intermolecular homocoupling of indole derivatives to give
2,20-biindolyl systems in good yields and with complete
Scheme 2 Scope of aldehydes. Conditions: Cp*Rh(MeCN)3(SbF6)2
(5 mol%), 1a (1 equiv), 2a or 2g–y (2 equiv), 3 A molecular sieves and
Ag2CO3 (2 equiv) were dissolved in the CH2Cl2 (0.1 M) and heated at
85 1C for 24 h in sealed tubes. Isolated yields are reported.
Scheme 3 Rhodium-promoted oxidative homocoupling of 1a.
c
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Scheme 4 Scope of indoles. Conditions: Cp*Rh(MeCN)3(SbF6)2
(5 mol%), 1g–n (1 equiv), 2a (2 equiv), 3 A molecular sieves and
Ag2CO3 (2 equiv) were dissolved in the CH2Cl2 (0.1 M) and heated at
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This work was supported by the National Science & Technology
Major Project ‘‘Key New Drug Creation and Manufacturing
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5163–5165 5165